Project Summary TRD 3 The overall goal of TRD 3 is to enable advanced OCT imaging, with high resolution and functional and dynamic contrast, inside the living body, through narrow diameter, rotational probes. Instruments and algorithms will be developed that overcome fundamental barriers, intrinsic to flexible, rotational fiber-optic probes, that have previously compromised image quality and prohibited the integration of functional and dynamic contrast. Specific Aim 1 addresses the need for functional imaging of blood flow in the coronary arteries. In catheter- based OCT a side-looking fiber-optic probe performs a helical scan pattern and records the reflectivity profile as a function of depth at each scan location. For normal imaging of the arteries, the blood is displaced by injecting a clear contrast agent. Recording, instead, time sequences without injection produces a rapidly fluctuating signal related to the blood flow. Based on accurate modeling of this signal, a reconstruction algorithm to extract vectorial blood flow profiles will be developed. Eliciting the overall flow rate offers a key parameter for the assessment of atherosclerotic lesions in human coronary arteries. Flow is also a critical factor in endothelial dysfunction and atherogenesis. The ability to map turbulence and detailed flow profiles offers a new avenue for the study of preclinical mouse models of atherosclerosis. Specific Aim 2 explores the polarization properties of biological tissue. Polarization sensitive detection measures the polarization state of the backscattered light. Combined with two orthogonal polarization states for illumination, this provides a complete characterization of the polarization properties of the tissue. However, the spinning catheter and the superimposed tissue impact and bias the polarization states at each depth. A reconstruction strategy to extract the depth-resolved polarization properties, including birefringence, optic axis and depolarization will be developed. Polarization contrast will help in differentiating between acute and chronic thrombus, which is an unresolved challenge in the clinical management of deep vein thrombosis, and in identifying different plaque types in atherosclerosis. Specific Aim 3 responds to the need for catheter-based imaging in preclinical small animal research. Narrow diameter rotational OCT probes, small enough to access the vascular system in small animals, or image interstitial tissue accessed through the bore of a hypodermic needle will be developed. The miniature probes will compensate the astigmatism originating from the transparent narrow diameter sheath that is protecting the spinning probe, and achieve a high quality and tight focus. Combined with a stable scanning mechanism this will enable high resolution imaging of the minute anatomy in the organs of small animals. Combined, these efforts will improve the diagnostic capability of OCT by providing additional contrast and functional parameters and expand the application of OCT to tissues and organs previously out of its reach.